Hemophilia A or B With Inhibitor
Conditions
Brief summary
The purpose of this multicentre, randomized, double-blinded, single dose, two-way cross-over study, is to compare the pharmacokinetics (PK) and pharmacodynamic (PD) of two different doses of the biosimilar eptacog alfa (activated) with Novoseven in 48 patients, adult and children (\>12 years), not bleeding, with hemophilia A or B with inhibitors. Patients will be randomized to receive either a single dose of eptacog alfa biosimilar 90 μg/kg or 270 μg/kg and one single dose of NovoSeven 90 μg/kg or 270 μg/kg, or vice versa, with doses separated by a washout period. All patients will be followed 12 months and will receive biosimilar eptacog alfa, on demand, for every bleeding episode that should occur - or - for prophylaxis, with the aim of monitoring of inhibiting antibody formation, lack of efficacy and collection of safety data.
Detailed description
Forty-eight patients enrolled, not bleeding, will be randomized to receive two injections separated by a washout period of 3 days (t1/2 = 2.3h). Patients are centrally registered and randomized to receive in a 2x2 cross-over setting either a single dose of two for the following products: A: AryoSeven 90 µg/kg and B: NovoSeven 90 µg/kg - or - C: AryoSeven 270 µg/kg and D: NovoSeven 270 µg/kg. Patients will be hospitalized at the time of study medication administration and plasma sampling. Before any treatment, a blood sample will be obtained in all patients for testing for immunogenicity.
Interventions
BIOLOGICALBiosimilar eptacog alfa, activated (AryoSeven)
A single dose of eptacog alfa biosimilar (AryoSeven) 90 μg/kg or 270 μg/kg. Then, in an open follow up phase of 12 months, for every bleeding episode patients will receive eptacog alfa biosimilar, on demand, for one of more days until resolution of bleeding, based on the Investigator's decision - or - prophylaxis with eptacog alfa biosimilar, with dose, frequency, and duration of treatment based on the Investigator's decision. The modality of treatment (on demand or prophylaxis) will be decided by the Investigator.
BIOLOGICALEptacog alfa, activated (Novoseven)
A single dose of eptacog alfa (Novoseven) 90 μg/kg or 270 μg/kg. Then, in an open follow up phase of 12 months, for every bleeding episode patients will receive eptacog alfa biosimilar, on demand, for one of more days until resolution of bleeding, based on the Investigator's decision - or - prophylaxis with eptacog alfa biosimilar, with dose, frequency, and duration of treatment based on the Investigator's decision. The modality of treatment (on demand or prophylaxis) will be decided by the Investigator.
Sponsors
AryoGen Pharmed Co.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Blinding will be performed by an independent third party operator (nurse/pharmacist, unblinded), who will prepare undistinguishable syringes with patient's dosing and labelling.
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of congenital hemophilia A or B with inhibitors to FVIII or FIX titer \>5 Bethesda Units (BU) * with \> 2 episodes of bleeding/year requiring treatment with FVII infusions, non in bleeding status * male subjects * adult and children (\>12 years) * written informed consent to the protocol to be eligible for the study. For minor patients, parent/legal guardian will provide consent and, when possible, patient assent will also be obtained. For compromised patients, their designated proxy must provide informed consent. * For the PK/PD phase, patients will be hospitalized at the time of study medication administration for plasma sampling (2 times during the study).
Exclusion criteria
* Any other type of congenital or acquired coagulopathy, such as liver disease (hepatitis), vitamin k deficiency, uremia, malignancy. * Antibodies against Factor VII * Ongoing bleeding prophylaxis regimens with Novoseven or planned to occur during the trial * Patients who have received routine (prophylactic) treatment with rFVIIa in the period between screening visit (visit 1) and visit 2 of this study (first dose administration) * Platelet count less than 100.000 platelets/microliter (at screening visit) * Any clinical sign or known history of an arterial thrombotic event or deep venous- thrombosis or pulmonary embolism * HIV positive with current CD4+ count of less than 200/µL * Liver cirrhosis * Factor VIII/IX immune tolerance induction regimen planned to occur during the trial * Known hypersensitivity to the study medication * Parallel participation in another experimental drug trial. * Parallel participation in another marketed drug trial that may affect the primary endpoint of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf) | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay (Diagnostics Stago, France). |
| Treatment response to Thrombin Generation Assay (TGA), D-Dimer, F1.2 prothrombin fragments. | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma levels based on standard methods recommended by the Subcommittee on the control of anticoagulation of the ISTH |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time of Cmax (tmax); | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
| Fraction of the total AUCinf that was derived by extrapolation beyond tlast (AUCextra) | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
| First order rate constant associated with the terminal (log-linear) portion of the curve (λz) | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
| Elimination half-life | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
| Area under the plasma concentration-time curve from 0 to the last measurable time point (AUClast). | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
| Clearance and CL/Dose (CL) | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
| Volume of distribution (Vss) | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
| Immunogenicity | On plasma samples obtained at screening visit, before the second dose/second drug administration, and then every 3 months for a year | The Prothrombin Time (PT) based Bethesda assay will be used. |
| Adverse Events | Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up. | Information about all adverse events, whether volunteered by the patient, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, will be collected, recorded and followed as appropriate. |
| Mean residence time (MRT) | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
| Maximum plasma concentration (Cmax) | Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay |
Countries
Iran, Turkey (Türkiye)
Outcome results
None listed